Department of Biology, Molecular Microbiology, University of Konstanz, 78457 Konstanz, Germany.
Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland.
Mol Cell. 2019 Sep 5;75(5):996-1006.e8. doi: 10.1016/j.molcel.2019.06.030. Epub 2019 Jul 31.
Cotranslational processing of newly synthesized proteins is fundamental for correct protein maturation. Protein biogenesis factors are thought to bind nascent polypeptides not before they exit the ribosomal tunnel. Here, we identify a nascent chain recognition mechanism deep inside the ribosomal tunnel by an essential eukaryotic cytosolic chaperone. The nascent polypeptide-associated complex (NAC) inserts the N-terminal tail of its β subunit (N-βNAC) into the ribosomal tunnel to sense substrates directly upon synthesis close to the peptidyl-transferase center. N-βNAC escorts the growing polypeptide to the cytosol and relocates to an alternate binding site on the ribosomal surface. Using C. elegans as an in vivo model, we demonstrate that the tunnel-probing activity of NAC is essential for organismal viability and critical to regulate endoplasmic reticulum (ER) protein transport by controlling ribosome-Sec61 translocon interactions. Thus, eukaryotic protein maturation relies on the early sampling of nascent chains inside the ribosomal tunnel.
新生多肽的共翻译加工对于蛋白质的正确成熟至关重要。人们认为蛋白质生物发生因子在新生多肽离开核糖体隧道之前就与它们结合。在这里，我们通过一种必需的真核细胞质伴侣蛋白在核糖体隧道内鉴定出新生链识别机制。新生多肽相关复合物（NAC）将其β亚基的 N 端尾巴（N-βNAC）插入核糖体隧道中，以便在靠近肽基转移酶中心的位置直接感知合成过程中的底物。N-βNAC 将生长中的多肽引导到细胞质中，并重新定位到核糖体表面上的另一个结合位点。我们使用秀丽隐杆线虫作为体内模型，证明 NAC 的隧道探测活性对于生物体的生存至关重要，并通过控制核糖体-Sec61 易位体相互作用来调节内质网（ER）蛋白运输。因此，真核生物蛋白质成熟依赖于核糖体隧道内新生链的早期采样。
